Project details

Total cost:

EU contribution:

Coordinated in:

Topic(s):

Funding scheme:

CSC - Cost-sharing contracts

Objective

The aim of the project is to generate novel hybrid molecules, potentially showing anti-tumour activity, by engineering several pathways involved in the biosynthesis of anti-tumour drugs by streptomycetes. The target drugs for engineering will be the angucyclines (urdamycins), the aureolic acid group (mithramycin, chromomycin and olivomycin), the anthracyclines group and elloramycin and tetracenomycin. Gene clusters (or specific genes) involved in the biosynthesis of these anti-tumour drugs will be isolated and sequenced to identify potential gene functions and they will be used for interspecific exchange experiments to create new hybrid gene constructions. Novel molecules synthesised by these clones will be identified, isolated and their structures elucidated. Mutants blocked at specific steps of the biosynthesis will be also generated by gene replacement techniques and the accumulated products isolated and structurally identified. These accumulated products will be used for directed biosynthesis of specific strains or mutants to generate new compounds. Gene clusters will be also introduced into a streptomycete strain able to synthesise fluoroacetate such that fluoroacetate may be used as starter unit to generate modified molecules. In addition, new molecules will be also generated by feeding specific strains with compounds derived from polyketide model systems. Potential cytostatic activity of the novel molecules will be assayed using different tumour cell lines. The experimental approach used in this proposal will be a co-ordinated, multi-disciplinary study using molecular biology, organic chemistry and cell cultures and will involve five university research groups and two small/medium sized enterprises. Achievements of the goal of the project will have important biotechnological implications and could directly benefit the european pharmaceutical sector interested in anti-tumour drugs.